DNA-PK in human malignant disorders: Mechanisms and implications for pharmacological interventions.

The DNA-PK holoenzyme is a fundamental element of the DNA damage response machinery (DDR), which is responsible for cellular genomic stability. Consequently, and predictably, over the last decades since its identification and characterization, numerous pre-clinical and clinical studies reported observations correlating aberrant DNA-PK status and activity with cancer onset, progression and responses to therapeutic modalities. Notably, various studies have established in recent years the role of DNA-PK outside the DDR network, corroborating its role as a pleiotropic complex involved in transcriptional programs that operate biologic processes as epithelial to mesenchymal transition (EMT), hypoxia, metabolism, nuclear receptors signaling and inflammatory responses. In particular tumor entities as prostate cancer, immense research efforts assisted mapping and describing the overall signaling networks regulated by DNA-PK that control metastasis and tumor progression. Correspondingly, DNA-PK emerges as an obvious therapeutic target in cancer and data pertaining to various pharmacological approaches have been published, largely in context of combination with DNA-damaging agents (DDAs) that act by inflicting DNA double strand breaks (DSBs). Currently, new generation inhibitors are tested in clinical trials. Several excellent reviews have been published in recent years covering the biology of DNA-PK and its role in cancer. In the current article we are aiming to systematically describe the main findings on DNA-PK signaling in major cancer types, focusing on both preclinical and clinical reports and present a detailed current status of the DNA-PK inhibitors repertoire

Infrared Spectra and Spectral Energy Distributions for Dusty Starbursts and AGN

We present spectroscopic results for all galaxies observed with the Spitzer Infrared Spectrograph (IRS) which also have total infrared fluxes f(ir) measured with the Infrared Astronomical Satellite (IRAS), also using AKARI photometry when available. Infrared luminosities and spectral energy distributions (SEDs) from 8 um to 160 um are compared to polycyclic aromatic hydrocarbon (PAH) emission from starburst galaxies or mid-infrared dust continuum from AGN at rest frame wavelengths ~ 8 um. A total of 301 spectra are analyzed for which IRS and IRAS include the same unresolved source, as measured by the ratio fv(IRAS 25 um)/fv(IRS 25 um). Sources have 0.004 < z < 0.34 and 42.5 < log L(IR) < 46.8 (erg per s) and cover the full range of starburst galaxy and AGN classifications. Individual spectra are provided electronically, but averages and dispersions are presented. We find that log [L(IR)/vLv(7.7 um)] = 0.74 +- 0.18 in starbursts, that log [L(IR)/vLv(7.7 um)] = 0.96 +- 0.26 in composite sources (starburst plus AGN), that log [L(IR)/vLv(7.9 um)] = 0.80 +- 0.25 in AGN with silicate absorption, and log [L(IR)/vLv(7.9 um)] = 0.51 +- 0.21 in AGN with silicate emission. L(IR) for the most luminous absorption and emission AGN are similar and 2.5 times larger than for the most luminous starbursts. AGN have systematically flatter SEDs than starbursts or composites, but their dispersion in SEDs overlaps starbursts. Sources with the strongest far-infrared luminosity from cool dust components are composite sources, indicating that these sources may contain the most obscured starbursts.Comment: Accepted for publication in The Astrophysical Journa

CAR T cell-based immunotherapy and radiation therapy: potential, promises and risks

Abstract CAR T cell-based therapies have revolutionized the treatment of hematological malignancies such as leukemia and lymphoma within the last years. In contrast to the success in hematological cancers, the treatment of solid tumors with CAR T cells is still a major challenge in the field and attempts to overcome these hurdles have not been successful yet. Radiation therapy is used for management of various malignancies for decades and its therapeutic role ranges from local therapy to a priming agent in cancer immunotherapy. Combinations of radiation with immune checkpoint inhibitors have already proven successful in clinical trials. Therefore, a combination of radiation therapy may have the potential to overcome the current limitations of CAR T cell therapy in solid tumor entities. So far, only limited research was conducted in the area of CAR T cells and radiation. In this review we will discuss the potential and risks of such a combination in the treatment of cancer patients

Evaluating the burden of brucellosis in hospitalized patients in Armenia, 2016

ObjectiveTo understand the disease burden, we studied the epidemiological and clinical characteristics and associated costs for brucellosis patients hospitalized in Nork hospital in 2016.IntroductionBrucellosis, endemic in Armenia, is recognized as a significant public health challenge with a major economic burden. To address the regional threat of brucellosis for both animal health and public health, the “One Health Surveillance of Brucellosis in Armenia” was initiated in December 2016. The project aims to develop scientifically sound strategies and policies for sustainable control of the disease.MethodsIn 2016, 265 patients diagnosed with brucellosis were hospitalized at “Nork” hospital, of whom 16 were 0-14 years old and 94% were males. Diagnosis was confirmed using agglutination test and ELISA. The SPSS program was used to analyze the data.ResultsDistribution of the disease by marz revealed that the most cases came from Ararat (53), followed by Kotayk (49), Armavir (38), Aragatsotn (36), Yerevan (28), Gegharkunik (26), Vayots Dzor (24), Syunik (8), and Lori (3). Clinical data indicated that 71% of patients had acute brucellosis with fever, arthralgia and night sweating while 29% suffered chronic brucellosis with damage of organ systems. The primary complaints included arthralgia (80%), sweating (60%) and fever (40%). Joint pain was mainly located in knee, elbow, and sacroiliac regions. Average grade of fever was 37,9±0,95oC. Total days spent in hospital were 1798, economic losses for the hospital were estimated at AMD 36 million per year.ConclusionsThose at the highest risk for brucellosis were males living in Ararat and Kotayk marzes who work with livestock.

p53-dependent treatment response to DNA-PK inhibition in combination with irradiation in head and neck squamous cell carcinoma models

Aims: M3814 is a small-molecule inhibitor of DNA-PK, a key regulator of nonhomologous end joining (NHEJ). Inhibition of NHEJ along with irradiation (IR)- induced DNA double-strand breaks can potentially increase antitumor treatment efficacy. This study aims to investigate responses of head and neck squamous cell carcinomas with distinct HPV and p53 status to the treatment with IR, DNA-PK inhibition, and their combination. Methods: Three groups of cell lines with various HPV/p53 genotypes (p53-wt/HPV–; p53-mutated/HPV–, and p53-wt/HPV+) were treated by M3814, 4 Gy IR, or a combination of M3814 and IR. In addition to viability and cell cycle assays, caspase 3 activity and senescence-associated β-galactosidase assays were used to evaluate cell fates such as apoptosis and senescence. yH2AX and RAD51 foci immunostainings at different time points were implemented to assess the levels of DNA damage and its repair. NMRI- nu mice with subcutaneous xenografts of p53-wt/HPV+ and p53-wt/HPV- cell lines were treated with either fractionated 10 Gy IR (delivered with the small animal radiation therapy system SmART) alone or in combination with orally distributed M3814. Results: Decreased number of viable cells after IR alone and particularly after combined treatment was observed in most of the cell lines. Inhibition of NHEJ combined with IR induces an abrogation of proliferation with different cell fates. Whereas HPV+ and p53-mutated cells undergo apoptosis due to a common alteration in the p53 pathways, p53-wt cells are preferentially eliminated through senescence. Elevated yH2AX foci formation after 24 and 48 h in the combination treatment group indicates unresolved persistent DNA damage. In vivo, significant effects of IR and of the combination treatment on tumor growth control were observed particularly in p53-wt/HPV+ xenografts. Conclusion: M3814 radiosensitizes HNSCC tumors and leads to better treatment response in dysfunctional p53 cells. Determination of the HPV and p53 status in a particular tumor might be necessary to effectively shape the intervention outcome when combining NHEJ targeting with radiation therapy

Study of neuroprotective activity of new acetylcholinesterase inhibitors TVA and TVS in experimental model of Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is a severe neurodegenerative disease characterized by loss of synaptic connection between neurons of the cortex and subcortical regions. The cholinergic deficit is a consistent and early finding in AD, hence acetylcholinesterase inhibitors (AChEIs) are used for symptomatic improvement of AD. Most of these therapeutic agents are hepatotoxic, leading to liver failure and other complications. Therefore, the study of new AChEIs with less toxic impact and better effectivity is a topical challenge. In view of this, we synthesized novel chemical compounds: TVA and TVS that possess AChEI activity and studied their neuroprotective effect in an experimental AD model. Materials and methods: Studies were performed on white rats. Acute toxicity studies were performed by Karber’s method. AD was induced via bilateral intracerebroventricular administration of Aβ 25–35. Histopathological examinations were performed in the hippocampus and the entorhinal cortex. Liver tissue was additionally examined to monitor the hepatotoxicity of these compounds. Results: Studies of the hippocampus showed that compared to control and TVA-treated groups, under the influence of TVS there were few morphological alterations. Experimental groups showed an increase in the glial cell count, compared to the intact animals. In comparison to the AD group, the increase in microglia was not that prominent under the action of the novel compounds. Under the influence of TVA and TVS, the entorhinal cortex was more susceptible to neuronal injury, although TVS protected pyramidal neurons. Also, the group treated with TVA had signs of acute liver damage, while under the influence of TVS there were no signs of liver changes. Discussion: Histopathological examination showed that the neurodegenerative processes in the hippocampus, as well as in the entorhinal cortex, were significantly reduced under the influence of TVS, compared with the control group. At the same time, TVA had no significant effect on the protection of neuronal cells. Also, TVS was less toxic, and there was no sign of hepatotoxicity during the experiments. Conclusion: These studies demonstrated that TVS possesses neuroprotective activity and reduces neuronal damage induced by Aβ. Graphical abstract

Barriers and drivers of positive COVID-19 vaccination behaviours among healthcare workers in Europe and Central Asia: a qualitative cross-country synthesis

Abstract Vaccination uptake is essential to controlling the ongoing COVID-19 pandemic. Healthcare workers (HCWs) play a critical role in receiving, recommending and delivering COVID-19 vaccination. Understanding the specific influences on each behaviour enables the development of targeted and tailored interventions to improve vaccination uptake. This paper presents a qualitative synthesis of HCWs’ individual and context barriers and drivers to these three vaccination behaviours across 10 countries in Europe and Central Asia. Qualitative data from interviews and focus group discussions with 378 HCWs between December 2020 and March 2022 were synthesised and organised by four COM (capability, physical and social opportunity, motivation) factors. Differences by stage of COVID-19 vaccine roll-out (in preparation, early and late delivery) were explored. Receiving vaccination related to all four factors. Recommending vaccination mostly related to capability and motivation. HCWs were generally well-informed by official sources and viewed vaccination as the way to end the pandemic, acknowledging their important role in this. Colleagues, family and friends were positive influences on personal vaccination decisions. However, knowledge gaps were evident, particularly amongst nurses who relied on (social) media. Concerns about safety and effectiveness, often connected to knowledge gaps, were heightened by the accelerated timeline for COVID-19 vaccine development and approval. This impeded some HCWs’ motivation to receive and recommend vaccination even in the later roll-out countries. Delivering vaccination was facilitated by support from public health organisations, teamwork and service re-organisation, more evident amongst later roll-out countries. Ongoing high workloads, stress and burnout hindered delivery. Complex and inter-related factors affecting HCWs’ vaccination behaviours were identified. These insights should inform the design of multifaceted interventions (e.g., communication skills training, management support for HCWs’ mental health, and engaging them in decision-making for service redesign); not only for COVID-19 vaccination as it is integrated into routine services but for routine immunization as a whole